With increasing awareness and published documentation, severe inaccuracies and unrealiability are associated with a variety of methods used to quantify histamine in biological fluids, including the commonly used radioenzymatic assay. We have also encountered severe problems with the radioenzymatic determination of urinary histamine in patients with mastocytosis which could not be readily rectified. Thus, we have recently developed a very accurate and sensitive method for the determination of urinary histamine using negative ion chemical ionization mass spectrometry. Examples of up to 20-fold differences in the levels measured by the two methods are demonstrated. Methods are proposed to develop GC/MS assays for the determination of the histamine metabolites, methylhistamine and methylimidazoleacetic acid, to enhance an accurate assessment of endogenous production of histamine. Previous studies have demonstrated that dietary factors can greatly contribute to the levels of histamine and its metabolites excreted in the urine which can diminish the accuracy of assessing endogenous histamine production by quantifying these compounds in biological fluids. Studies are outlined to establish the normal levels of histamine and its metabolites in plasma and urine under varied conditions of strict control of potential dietary influences using the developed accurate methodology. The existence of possible alterations in the metabolism of histamine in mastocytosis will be investigated. Whether dietary modifications and control can enhance the accuracy and sensitivity of determining increased endogenous production of histamine of mast cell origin by quantification of urinary histamine and its metabolites will be investigated in patients with mastocytosis. Development of accurate methodology to determine histamine and its metabolites in biological fluids and accurate information on dietary factors which can alter the levels of these compounds would contribute in a valuabale way to investigations of immediate hypersensitivity and to the biochemical diagnosis of patients with mastocytosis, a disease recently shown to be extremely more common than previously recognized.